Hantaviruses (Bunyaviridae: Hantavirus) are lipid-enveloped, minus-sense RNA viruses. The RNA of the viral genome is tripartite, consisting of three fragments generally designated as S, M and L for small, medium and large genome fragments, respectively. The M segment encodes a precursor protein that is processed to form the two envelope glycoproteins, termed G1 and G2. The S segment encodes a nucleocapsid protein, termed N which forms the filamentous helical nucleocapsid of the virus and elicits the humoral response. The L segment of the genome encodes an RNA-dependent RNA polymerase (RDRP). Over 20 distinct hantaviruses are found in association with specific rodent or insectivore hosts worldwide. Their modes of transmission to humans, natural reservoirs, and the clinical features of human infection have been reviewed (see, e.g., Mertz et al., Adv. Internal Med. (1997) 42:369-421).
Hantavirus pulmonary syndrome (HPS), also known as hantavirus cardiopulmonary syndrome (HCPS) is an acute febrile illness with up to a 50% mortality rate. Patients present with nonspecific symptoms and progress rapidly to fulminant pulmonary edema and cardiovascular collapse. The predominant agent of HPS in North America is Sin Nombre virus (SNV; also known as Four Corners virus and Muerto Canyon virus). (Song et al., Lancet (1994) 344:1637; Khan et al., J. Med. Virol (1995) 46:281-286; Kahn et al., Am. J. Med. (1996) 100:46-48; Morzunov et al., J. Virol (1995) 69:1980-1983; Rollin et al., J. Med. Virol (1995) 46:35-39; Centers for Disease Control and Prevention, Morbid. Mortal. Weekly Rep. (1993) 43:45-48). At least three other hantaviruses have been associated with HPS in North America, including New York virus (NYV), Black Creek Canal virus (BCCV) and Bayou virus (BAYV).
Worldwide, a larger toll of illness is caused by the Eurasian hantaviruses that cause hemorrhagic fever with renal syndrome (HFRS). HFRS-associated viruses include Hantaan (HTNV), Puumala (PUUV), Seoul (SEOV), and Dobrava-Belgrade (DOBV) viruses (Lee et al., J. Infect. Dis. (1978) 137:298-308; Lee, et al., J. Infect. Dis. (1982) 146:638-644; Lee et al., J. Infect. Dis. (1982) 146:645-651; Brummer-Korvenkontio et al., J. Infect. Dis. (1980) 141:131-134). Clinical manifestations of HFRS are generally most severe for HTNV and DOBV infections, whereas PUUV infection is associated with a milder form of HFRS, nephropathia epidemica (NE), occurring in Scandinavia, Finland, Western Russia and Central Europe. Mortality rates of up to 20% have been reported from the most severe forms of HFRS.
Among the HFRS-associated hantaviruses, HTNV, SEOV and DOBV are antigenically similar. The HPS-associated viruses are also closely related to one another, and cross-react with PUUV. Antigenic cross-reactivity is most pronounced among the viral N proteins. In recombinant antigen diagnostic assays, the viral N antigen is dominant over the viral glycoproteins. Antibodies to the N antigen arise early in the course of infection and are universally detectable in convalescence. All persons with acute SNV infection have detectable antibodies against the SNV N antigen of the IgM class by the onset of clinical symptoms, and almost all have IgG antibodies directed against the N and G1 antigens (Bharadwaj et al., J. Infect. Dis. (2000) 182:43-48). SNV G1 antibodies are not reactive with the G1 antigens of other hantaviruses (Jenison et al., J. Virol. (1994) 68:3000-3006; Hjelle et al., J. Gen. Virol. (1994) 75:2881-2888).
Hantaviruses are transmitted to humans via inhalation of virus-contaminated aerosols of rodent saliva, urine and feces. A worker can contract hantavirus infection merely by entering into a room with infected rodents, which strongly supports the prevailing view that hantaviruses are transmitted through the air. This observation is also supported by a recent epidemiologic investigation showing that indoor exposures are extremely common. Person-to-person transmission has been demonstrated for the Andes virus (ANDV) in Argentina and is likely to be responsible for two family clusters in Chile. The virus may also be transmitted after rodent bites and possibly through ingestion of contaminated food or water.
All species of hantavirus appear to be primarily associated with a specific rodent host. There are three broad groups of hantaviruses and they are associated with the rodent subfamilies of Murinae, Arvicolinae and Sigmondontinae. The phylogenetic relations among rodents in these various subfamilies parallel, for the most part, the phylogenetic and antigenic relations of viruses associated with each particular reservoir. Each of these groups of hantaviruses contains one or more species or types that are known human pathogens. Information concerning the various hantaviruses is presented in Table 1.
TABLE 1HantavirusIdentityAssociatedSubfamilyVirusDiseaseAnimal HostLocationMurinaeHantaanHFRSApodemus agrariusAsia, Far EastRussiaDobravaHFRSA. flavicollisBalkansA. agrariusEuropeSeoulHFRSRattus norvegicusWorldwideR. rattusPuumalaHFRSCleothrianomysEuropeglareolusSigmodontinaeSin NombreHCPSPeromyscusWest andmaniculatusCentral US(grassland form)and CanadaMonongahelaHCPSP. maniculatusEastern US(forest form)and CanadaNew YorkP. leucopusEastern US(eastern halotype)Blue RiverHCPSP. leucopusCentral US(SN/NWhalotypes)BayouHCPSOryzomys palustrisSouthwestern USBlack CreekHCPSSigmondonFloridaCanalhispidus (eastern form)MuleshoeS. hispidusSouthern US(western form)CanoS. alstoniVenezuelaDelgaditoAndesHCPSO. longicaudatusArgentina andChileOranHCPSO. longicaudatusNW ArgentinaLechiguanasHCPSO. flavescensCentralArgentinaBermejoO. chacoensisNW ArgentinaHu39694HCPSUnknownCentralArgentinaPergamnoAkadon azaraeCentralArgentinaMacielBolomys abscurusCentralArgentinaLaguna NegraHCPSCalomys lauchaParaguay andBoliviaJuquitibaHCPSUnknownBrazilRio MamoreOligoryzomysBoliva andmicrotisPeruEl MoroReithrodontomysWestern USCanyonmegalotisand MexicoRio SegundoR. mexicanusCosta RicaArvicolinaePropect HillMicrotusN AmericapennsylvanicusBloodlandM. ochrogasterN AmericaLakeProspect Hill-M. pennsylvanicus/N Americalikemontanus/ochrogsterIsla VistaM. californicusWestern USand Mexico
Significant strides have been made in the management of hantavirus infection, but successful management requires that patients be diagnosed before the immediate preagonal stage of illness. Advances in tertiary care management have occurred that may reduce mortality due to hantavirus infection. However, since infection progresses very rapidly, these advances are likely to affect the prognosis only of those patients for whom a diagnosis can be made in a timely manner. A method for rapid detection of hantavirus antibodies appropriate for a rural setting and that could be applied during the early stages of illness could improve the prospects for early intervention.
Several assays have been attempted for the timely diagnosis of hantavirus infection. For example, a variety of formats for serologic diagnosis of hantavirus infection have been employed including bead agglutination, immunofluorescence and immunoprecipitation assays using laboratory-cultivated viruses, hemagglutination inhibition, plaque- and focus-reduction neutralization assays, and ELISA formats (Lee et al., J. Infect. Dis. (1978) 137:298-308; Lee et al., J. Infect. Dis. (1982) 146:638-644; Lee et al., J. Infect. Dis. (1982) 146:645-651; Lundkvist et al., Clin. Diagnos. Lab. Immunol. (1995) 2:82-86; Chu et al., Virology (1994) 198:196-204; Elgh et al., J. Med. Virol (1995) 45:146-150).
Strip immunoblot assays have also been used in an attempt at efficient diagnosis of hantavirus infection (see, e.g., Hjelle et al., J. Clin. Microbiol. (1997) 35:600-608; Bharadwaj et al., J. Infect. Dis. (2000) 182:43-48; Yee, et al., J. Wildl. Dis. (2003) 39:271-277). However, a universal assay for identifying multiple strains of hantaviruses is not currently available.
The wide-spread availability of an accurate, efficient and rapid assay for hantavirus infection would be highly desirable and could save a considerable number of lives.